Alcohol use disorders are associated with considerable morbidity and mortality. Amongst the most prominent correlates of liability to AUDs is age at first drink (AFD) and other drinking milestones, such as age at first intoxication (AFI) and age at first regular drinking (AFR). Early-onset drinkers are at 2-6 increased odds of subsequent alcohol-related problems, AUDs and other related harms (e.g. motor vehicle accidents). Despite overwhelming support for a link between AFD and AUDs, the mechanism underlying the association remains controversial and, importantly, genetically informative studies of this relationship are limited. Multiple genetically-informative hypotheses can be posited to explain this relationship: (a) AFD and AUDs have shared etiologies with overlapping genetic and environmental factors contributing to them; (b) AFD has a causal influence on AUDs (after accounting for shared etiologies); and more recently, (c) even after accounting for shared etiologies, AFD moderates the role of heritable influences on AUDs. Each of these hypotheses bear unique public health implications and understanding which mechanisms play the most prominent role in the etiology of AUDs would be substantially informative in future prevention and intervention efforts targeted at reducing the burden of early AFD. One approach that unifies these competing hypotheses is that of gene- environment interplay, including gene-environment correlation and interaction. In this secondary data analysis R21, we examine, using latent (twin) and measured (genomic) existing genetically informative data, the links between AFD, AFI, AFR and AUDs. The specific aims are: (a) to identify using twin data, the extent to which heritable factors influencing AUD are modified by AFD, AFI and AFR; (b) to examine whether after accounting for shared etiologies, AFD, AFI and AFR moderate (i.e. gene x environment interaction, or GxE) the extent to which candidate gene variants, both individually and as a polygenic risk score, influence AUD; and (c) to use genomewide association data, in an exploratory fashion, to identify novel genetic polymorphisms associated with AUD, via GxE, as a function of AFD, AFI and AFR. The strengths of this proposal include the use of multiple twin datasets, representing distinct and overlapping cohorts and including both males and females, which will allow us to validate our finding across samples from different cultures and birth cohorts, independent samples for meta-analysis of single SNP and polygenic scores from candidate gene and genomewide association analyses. Results from this R21 will be used to develop a program of research into the molecular, cellular and neurobiological mechanisms that may be associated with or disrupted by early exposure to alcohol. From a public health perspective, results from this proposal can inform strategies for reducing transitions to problem drinking and AUDs by identifying the routes through which AFD, AFI and AFR impact vulnerability to AUDs.